Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
  • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• the present invention relates to an antiestrogenic drug applicable in particular to the treatment of certain forms of tumors, in particular of the mammary gland in its hormone-dependent forms.
• an anti-estrogen which can be administered by the oral route known as tamoxifen
• tamoxifen is known and is constituted by 1 (pB-dimethylaminoethoxypenyl) -trans-1,2-diphenylbut-1-ene, which is marketed under the name " Nolvadex ".
• Nolvadex 1 (pB-dimethylaminoethoxypenyl) -trans-1,2-diphenylbut-1-ene
• tamoxifen administered orally transforms during its hepatic passage into numerous metabolites including 1- (pB-dimethyl-amino-ethoxyphenyl) -trans-1- (p-hydroxyphenyl-2- diphenylbut-1- ene, or 4-hydroxytamoxifene, which is the active form of the product at the molecular level, but this 4-hydroxy derivative directly administered orally would be degraded faster than tamoxifen, hence the uselessness of its administration by this route.
• the 4-hydroxy derivative is twenty to one hundred times more active than tamoxifen as an antiestrogen at the estrogen receptors.
• oral or parenteral administration other than percutaneous results in a diffusion of this product throughout the body, causing - among other things - a paradoxical harmful stimulation of the ovaries.
• the 4-hydroxytamoxifen derivative has moreover been described as an antiestrogenic agent with a view to its administration by oral or possibly parenteral route, itself limited to injection.
• oral administration appears to be of limited effectiveness due to the destruction of the compound itself via the liver, while injection, leading to the introduction of said compound into the bloodstream, can induce the harmful ovarian actions previously indicated, by systemic effect.
• the antiestrogenic drug according to the invention derived from tamoxifen, the active product of which consists of 1- (pB-dimethylaminoethox-yphenyl) -trans-1 (p-hydroxyphenyl) -2-phenylbut-1-ene called 4-hydroxytamoxi -fene is presented in a hydroalcoholic gel which can be administered by percutaneous route, preferably locoregional and pharmacologically acceptable.
• progesterone binds to its own receptor which it activates.
• progesterone and estrogen are antagonistic in their 4-hydroxytamoxifene
• tracer doses of tritiated 4-hydroxytamoxifene applied in alcoholic solution 24 hours before the removal of cancerous breasts were assessed for 4-hydroxytamoxifene.
• 4-hydroxytamoxifene is found in its original form at the level of protein structures corresponding to hormone receptors. It is therefore capable of having at this level an antiestrogenic activity. A small part of the radioactivity is metabolized into unidentified products (3%).
• the same product was applied to the skin of a healthy subject in radioactive form and the radioactivity found in the urine was calculated within 15 days of administration of the product.
• the rate of urinary elimination shows a weak and progressive destruction of the product.
• traces of the product are detectable - there is therefore no accumulation. It is only secondarily that it reaches the liver where it is inactivated.
• progesterone was taken up by specific receptors and that it is largely inactivated in situ.
• the fact that 4-hydroxytamoxifen and progesterone are soluble in alcohol and absorbable by the skin allows the presentation in an alcoholic gel suitable for percutaneous administration, the applicants' work showing a skin absorption coefficient of 10% for progesterone and close to 1% for 4-hydroxytamoxifene.
• the alcoholic gel comprises, in addition to progesterone and 4-hydroxytamoxifene, various excipients necessary for conditioning and allowing percutaneous penetration, in particular "Carbopol" ®, ethyl alcohol and water.
• the daily doses of product to be administered are easy to calculate based on the absorption coefficients of the drugs and the doses which it is desired to obtain for 4-hydroxytamoxifen and progesterone at the level of their receptor molecules.
• a formulation of a gel in accordance with the invention for percutaneous administration is given below, by way of non-limiting example:
• Carbopol 934" ® is a carboxyvinyl polymer with active carboxylic groups, helping to form stable emulsions with the amines).
• the medicament described finds its application in the treatment of affections of the breast, in particularly of benign or even cancerous affections of the breast.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Dermatology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Inorganic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicinal Preparation (AREA)
• Steroid Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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• 1984
  • 1984-01-20 FR FR8400927A patent/FR2558373B1/fr not_active Expired
  • 1984-12-19 EP EP84201920A patent/EP0151326B1/fr not_active Expired
  • 1984-12-21 JP JP60500495A patent/JPH0667826B2/ja not_active Expired - Fee Related
  • 1984-12-21 US US06/777,786 patent/US4919937A/en not_active Expired - Lifetime
  • 1984-12-21 WO PCT/EP1984/000436 patent/WO1985003228A1/fr active IP Right Grant
  • 1984-12-21 EP EP85900469A patent/EP0169214B1/fr not_active Expired - Lifetime
  • 1984-12-21 DE DE8585900469T patent/DE3485581D1/de not_active Expired - Lifetime
  • 1984-12-21 AT AT85900469T patent/ATE73334T1/de not_active IP Right Cessation
• 1985
  • 1985-09-17 DK DK420385A patent/DK155143C/da active

Non-Patent Citations (2)

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